JP2008500074A - Method and apparatus for decoupling and / or desynchronizing brain neuronal activity - Google Patents

Abstract

  The present invention relates to a device that decouples and / or desynchronizes activity synchronized to brain abnormalities. In this device, according to the invention, activity in a partial region of the brain region or in a functionally related brain region is stimulated by the electrodes. As a result, the affected neurons in the abnormal area are decoupled and desynchronized, and the patient's symptoms are suppressed. In another implementation of the device, brain activity that synchronizes with anomalies due to disease is made asynchronous to suppress symptoms. As a result, a feedback stimulus signal, ie, measured, time delayed and processed neuronal activity is used. In this case, the stimulation signal is controlled according to the present invention in an autonomous control manner as required. As a result, the intensity of the resulting stimulus effect on the group of neurons to be decoupled or the group of neurons to be desynchronized is automatically minimized after a successful decoupling and / or desynchronization. In order to operate without problems, the device does not require complex calibration or control of stimulation parameters, but these are preferably adapted and optimized by additional control systems. The device is operated by a control system so that the stimulation electrode (2) and at least one sensor (3) are decoupled and / or asynchronous in their local surroundings. It has two sensors (3).

Description

  The present invention relates to a method and device for decoupling and / or asynchronizing brain neuronal activity according to the superordinate concept of claim 1.

  For example, an abnormal synchronization activity of the brain with its occurrence in the basal ganglia can cause synchronization as an activity in subsequent areas such as the motor cortex. This secondary synchronization is significantly involved in the development of abnormal symptoms. The present invention relates to an apparatus that makes it possible to remove active abnormal activity from a subsequent area. This can reduce abnormal symptoms. In another embodiment, the device of the present invention can also be used for asynchronous, i.e. rhythmic collective activity or firing of neurons in an abnormally synchronized group of neurons. A group of nerve cells is called an activity group.

  For example, in patients with neurological or psychiatric illnesses such as Parkinson's disease, essential tremor, ataxia or obsessive-compulsive disorder, in the brain, such as certain areas of the thalamus or basal ganglia A neuron group is abnormally active, for example, is oversynchronized. In this case, a large number of neurons generate action potentials synchronously; the involved neurons fire excessively synchronously. In a recovering patient, neurons in these brain regions are characteristically different, eg, fire independently. This brain activity synchronized with the abnormality changes the neuronal activity in another brain region, for example, in the cerebral cortex like the primary motor cortex. In this case, activity synchronized with thalamic and basal ganglion abnormalities forces the cerebral cortex to align with its rhythm. As a result, the muscles controlled by these regions eventually cause abnormal activity, such as rhythmic tremor.

  In patients who can no longer be treated with medication, depth electrodes are implanted unilaterally or bilaterally depending on the condition and whether the disease is unilateral or bilateral. . In this arrangement, the cable is laid on a so-called generator from under the skin of the head. This generator consists of a control device with a battery, for example implanted in the area of the clavicle under the skin. Individual stimuli, for example continuous stimuli (pulse trains with a frequency greater than 100 Hz) with a high-frequency periodic sequence of rectangular pulses, are performed through the depth electrode. The purpose of this method is to suppress the firing of neurons in the target area. The mechanism of action based on standard depth stimulation is not more fully described. The results of many studies show that standard depth stimuli act like restorable (tissue) disorders, ie act like restorable exclusion of tissues: standard depth stimuli are within the target area And / or suppress firing of neurons in the brain region connected to it.

  The disadvantage of this stimulation form is that the generator energy consumption is very high. As a result, generators containing batteries need to be frequently replaced by surgery after only about 1-3 years. A further disadvantage is that high-frequency continuous stimulation can adapt the group of neurons over the course of several years as an antiphysiological (abnormal) input in the brain, for example in the area of the thalamus or basal ganglia. In order to obtain the same stimulation result, it is necessary to stimulate with a higher stimulation amplitude as a result of this adaptation. The greater the stimulus amplitude, the greater the stimulation of the adjacent area, the grammatical disorder (speech disorder), perceptual dysfunction (in some cases, very painful abnormal perception), cerebellar ataxia (third party There is a high probability of side effects such as inability to exist without support) or schizophrenia. These side effects cannot be tolerated by the patient. In these cases, therefore, the therapeutic efficacy disappears after several years.

  German Patent Application No. 102 11 766.7 “Apparatus for treating a patient by brain stimulation, electronic components and medical use of this device and this electronic component”, German Patent Application No. 103 18 071.0- No. 33 “A device for asynchronous brain neuron activity” and German patent application No. 103 18 071.0 “A device for stimulating the brain with multiple electrodes to treat time delay” In the case of other stimulation methods, it is proposed that a demand-controlled stimulus is applied in each target area. The purpose of this method and this device is to approximate a physiologically correlated firing pattern rather than simply suppressing firing that is synchronous to anomalies-as is the case with standard depth stimuli. This reduces power consumption on the one hand and, on the other hand, demand-controlled stimulation reduces energy input into the tissue compared to standard depth stimulation. However, these request controlled and asynchronous methods also have associated drawbacks.

The disadvantages of the stimulation method which makes desynchronization as required according to German Patent Application No. 102 11 766.7 are due to the following facts: to synchronize a group of synchronized neurons with electrical stimulation, for a certain period of time. Electrical stimulation must be accurately applied to a particular phase of abnormal rhythmic activity within the target area. Since such accuracy cannot be reliably achieved experimentally at present, synthesized stimuli are used. The first stimulus of such a synthesized stimulus controls the dynamic characteristics of the nerve cell group to be made asynchronous by resetting, that is, restarting. On the other hand, the second stimulus of the synthesized stimulus is applied to the nerve cell group in a fragile state to make it asynchronous. However, for this, it is indispensable that the control property, that is, the reset property is sufficient. This particularly leads to strong stimuli need to be used for reset. However, this must be prevented in order to avoid side effects. However, it is more important that the desired asynchronous action occurs only when the stimulation parameters, i.e. the duration of the individual stimulation and in particular the interval between the first and second stimulation, are optimally selected. This has serious consequences:
1. A time-consuming calibration procedure is required. This calibration procedure generally lasts longer than 30 minutes.
2. Due to the time-consuming calibration procedure, the effect of desynchronizing stimulation according to German Patent Application No. 102 11 766.7 is utilized for the intraoperative selection of the most suitable target point for a depth electrode. I don't get it. Therefore, the effect of desynchronizing stimuli according to German patent application 102 11 766.7 needs to be examined separately for different target points; Increase the period of implantation.
3. When the characteristics of the network change more greatly, that is, when parameters such as synaptic strength and firing rate, which indicate the activity of the nerve cell group, change more greatly, recalibration is necessary.
4). The desynchronization stimulus according to DE 102 11 766.7 is effective only when the frequency of the neuron cell group to be desynchronized does not vary much more, so for example a short term due to a drastically changing frequency during drought. It cannot be applied to diseases with abnormally excessive synchronous activity during.

  The disadvantages of the demand controlled and desynchronized stimulation method according to DE 103 18 071.0-33 are due to the fact that: multiple electrodes are used to synchronize synchronized neuronal cells by electrical stimulation. Stimulation is carried out. A short-term high-frequency pulse train or low-frequency pulse train is applied to the individual electrodes. This phase resets the stimulated group of neurons. The points of time stimulated by these different electrodes are selected so that equally spaced phase shifts occur between the neural subpopulations assigned to the stimulation electrodes. After the end of the stimulation provided by such a large number of electrodes, complete asynchrony automatically starts due to the abnormally elevated mutual influence between neurons.

This method has the advantage of being fast calibration and robust against parameter variations. This stimulation method can therefore be used even when synchronous activity with a drastically changing frequency occurs only for a short period of time. Furthermore, the method according to German patent application 103 18 071.0-33 has serious drawbacks:
1. The essence of the method described in German Patent Application No. 103 18 071.0-33 is the application of a global stimulus that is repeated and possibly controlled. The stimulated tissue resynchronizes between the global stimulus and the global stimulus. This leads to the non-asynchronous neuron group swinging between two anti-physiological states, the N cluster state and the resynchronization transition state. In this case, N indicates the number of electrodes used for stimulation. Therefore, the neuron group to be asynchronous is not in an asynchronous state to be obtained for a longer period. However, this can be achieved to reduce the side effects associated with the symptoms and stimuli associated with the disease.
2. The on-demand control described in German Patent Application No. 103 18 071.0-33 has complicated control electronics and inevitably requires costly controls that exhibit higher energy consumption. To do.

  The stimulation method described above uses a single pulse, a high-frequency pulse train, and a low-frequency pulse train as stimulation signals. They modulate the dynamic properties of the neurons to be stimulated—especially the phase dynamic properties, for example, a group of neurons that are to be made asynchronous into an N cluster state by phase reset. These stimulation pulse trains are constructed without using the dynamic characteristics inherent to the group of neurons to be asynchronous, and in this sense are heterogeneous and antiphysiological signals for the group of neurons to be asynchronous. In order to suppress abnormal symptoms, it is necessary to apply a high-intensity stimulation pulse train. This leads to adaptation of the neuron group to be asynchronous to antiphysiological stimuli and possibly possible side effects.

The method described in German Patent Application No. 103 18 071.0 “A device for treating a patient by stimulating the brain with time delay with multiple electrodes” also has drawbacks:
1. At least two electrodes need to be used for stimulation.
2. The electrodes need to be configured primarily as depth electrodes. Thus, for example, there is a high risk of brain tissue damage during implantation of the depth electrode for the patient.

For the stimulation method described above, it is necessary to use one or multiple depth electrodes. This means high surgical costs and a great risk of complications such as brain tissue damage or cerebral hemorrhage that can occur during implantation of depth electrodes for the patient. This risk must be reduced in terms of successfully repairing the patient and reducing side effects.
German Patent Application No. 102 11 766.7 German Patent Application No. 103 18 071.0-33 German Patent Application No. 103 18 071.0

It is an object of the present invention to provide a device for decoupling and / or asynchronizing brain neuronal activity. Patients with abnormally synchronized brain activity can be treated gently and efficiently with this device. In this case, adaptation to an antiphysiological sustained stimulus must be prevented. A long calibration process must be prevented. Stimulation must be successful even when the main frequency component of abnormal rhythmic activity fluctuates violently. In addition, the device must achieve sustained decoupling and / or asynchrony. Antiphysiological conditions associated with transient stimuli must be largely prevented. The apparatus of the present invention does not require additional request control so that it can be selectively added as described in Section 6.3. Therefore, the apparatus of the present invention is technically easily feasible, requires little complex control electronics, and therefore consumes little power. The stimulator of the present invention must save power and function. As a result, it is not often necessary to surgically replace the stimulator battery implanted in the patient. In particular, since only one electrode needs to be implanted, and this electrode is implanted in a brain area that can be easily accessed in the following cases, such as an electroencephalogram electrode in the area of the motor area, the device of the invention. Is significantly improved compared to the above-described depth brain stimulation method. For brain stimulation, i.e. in particular-in a particular embodiment of the device according to the invention-a depth electrode is not necessary. As a result, there is no risk of bleeding during surgery due to arterial injury.

  The object of the invention is solved by the features described in the characterizing part of claim 1, starting from the superordinate concept of claim 1. By using the measured and processed activity of the neurons to be decoupled and / or desynchronized as a feedback stimulus signal, see Chapter 3, this task is In order to be completely decoupled and / or desynchronized, the activity of the neuron is influenced each time by a stimulating electrode with a feedback stimulus signal. This significantly reduces symptoms in the case of patients. In the case of another embodiment of the device of the invention as noted in Chapter 8, this device can also be used, for example, to synchronize active neurons. In this embodiment, the measured and processed neuronal activity of the active neuron group is applied through the stimulation electrode as a feedback stimulation signal. As a result, direct or indirect stimulation of the active group of neurons is performed by the feedback stimulation signal. This affects the group of neurons that should be asynchronous so that complete asynchrony occurs. This suppresses symptoms associated with the disease. Therefore, the device of the present invention has a control device 4. The control device 4 receives a measurement signal of one or a plurality of sensors 3, generates a stimulation signal from this signal, and applies this stimulation signal to the electrode 2 as a stimulation.

  The device of the present invention operates with power savings. As a result, it is not necessary to frequently replace the battery implanted in the patient.

  The device of the present invention enables the effect of selecting the optimal target point for the electrode obtained during surgery by the decoupling stimulus. When a depth brain electrode is used as electrode 2, the test stimulus and / or retrieval of the feedback signal is stepped in millimeters by the device of the present invention within the anatomically pre-calculated target point area during implantation of the electrode. Will be implemented first. The target point that can achieve the optimal therapeutic effect is selected as the target point for sustained implantation.

  In addition to the illnesses described above, which have activity that synchronizes to anomalies that often persist at a relatively constant frequency, illnesses that cause activity to synchronize with anomalies only intermittently (occurring in a short period of time) can be treated. The main indication is the treatment of hemorrhoids that can no longer be treated with drugs. The device of the present invention suppresses symptoms of, for example, Parkinson's disease, essential tremor, ataxia, epilepsy, depression and obsessive compulsive disorder.

  Other preferred configurations of the invention are described in the dependent claims.

  The drawings illustrate exemplary embodiments of the invention.

  FIG. 1 shows the apparatus of the present invention.

FIG. 2 shows the decoupling effect of a stimulus by a stimulus as described in Example 1 of Chapter 8.1. For illustration purposes, in FIGS. 2a-2d, the coupling is started for a time point of 4 seconds. Stimulation starts for time 7.5 seconds.
FIG. 2a: Time course of neuronal activity of the group of neurons to be decoupled during the uncoupled state as measured by sensor 3, during coupling and during stimulation.
FIG. 2b: Time course of firing pattern of neurons to be decoupled in the uncoupled state, during coupling and during stimulation.
FIG. 2c: Time course of the degree of synchronization of the neurons to be decoupled during the stimulation interval. Smaller values correspond to smaller synchronizations. Larger values correspond to strong synchronization.
FIG. 2d: Time course of the effect of the stimuli occurring on the group of neurons to be decoupled. That is, the sum of the coupling effect and the stimulus effect.
Fig. 2e: Distribution of firing frequency before coupling (left), distribution of firing frequency during coupling (center), and distribution of firing frequency at the start of stimulation (right).

FIG. 3 shows the decoupling effect of a stimulus by a stimulus as described in Example 2 of Chapter 8.1. For illustration purposes, in FIGS. 3a-3d, the coupling is started for a time point of 4 seconds. Stimulation starts for time 7.5 seconds.
FIG. 3a: Time course of neuronal activity of the group of neurons to be decoupled during the uncoupled state as measured by the sensor 3, during coupling and during stimulation.
FIG. 3b: Time course of firing pattern of neurons to be decoupled in the uncoupled state, during coupling and during stimulation.
FIG. 3c: Time course of the degree of synchronization of the group of neurons to be decoupled. Smaller values correspond to smaller synchronizations. A large value corresponds to a large synchronization.
FIG. 3d: Time course of the effect of the stimuli occurring on the group of neurons to be decoupled. That is, the sum of the coupling effect and the stimulus effect.
Fig. 3e: Distribution of firing frequency before coupling (left), distribution of firing frequency during coupling (middle) and distribution of firing frequency at the start of stimulation (right).

  FIG. 4: Schematic diagram of the coupling between a group of neurons 1 that synchronize with an active anomaly and a group of neurons 2 that are being decoupled. The neuron group 2 exemplarily shows a premotor area and / or a motor area.

  2a-d and 3a-d, the abscissa represents the time axis in seconds. On the other hand, along the ordinate, the measured neuronal activity (Figs. 2a, 3a) or firing pattern (Figs. 2b, 3b) or the degree of synchronization (Figs. 2c, 3c) or the effects of coupling and stimulation The sum (FIGS. 2d, 3d) is plotted in arbitrary units in each case. Neuronal activity measured by the sensor 3 (FIGS. 2a, 3a) is used as a reference for generating a stimulus. In FIGS. 2e and 3e, the abscissa indicates the frequency. The ordinate indicates the relative number of neurons having the corresponding frequency.

  The apparatus of FIG. 1 has an isolation amplifier 1. The isolation amplifier 1 is connected to an electrode 2 and at least one sensor 3 for detecting a physiological measurement signal. The electrode 2 used may be an electroencephalogram electrode or a brain electrode, for example. The isolation amplifier is also connected to a device 4 that processes and controls the signal. This device 4 is connected to an optical transmitter 5 for stimulation. The optical transmitter 5 is connected to an optical receiver 7 through an optical fiber 6. The optical receiver 7 is connected to a stimulator 8 that generates a signal. The stimulation device 8 that generates this signal is connected to the electrode 2. A relay 9 or transistor is present in the input region of the electrode 2 in the direction of the isolation amplifier 1. The device 4 is connected to a telemetry transmitter 11 via a conductor 10. This telemetry transmitter 11 is connected to a telemetry receiver 12. This telemetry receiver 12 is located outside the device to be implanted. A means 13 for displaying, processing and storing data is connected to the telemetry receiver 12. The sensor 3 used may be, for example, an electroencephalogram electrode, a brain electrode or a surrounding electrode.

  The electrode 2 may be any electrode known to those skilled in the art and suitable for application of the present invention. In the broad sense of the present invention, therefore, an electrode is an object that can be applied to the stimulation of the present invention.

  The electrode 2 is, for example, at least two wires. A potential difference is applied across the wires for stimulation purposes. The electrode 2 may be a macro electrode or a micro electrode. Alternatively, the electrode 2 may be a single wire. In this case, the potential difference is applied between the single wire and the metal part of the generator housing for stimulation purposes. Furthermore, although not forced, a potential difference can be measured by electrode 2 to record neuronal activity. In another embodiment, the electrode 2 may be composed of more than two wires. These wires can be used for measuring and stimulating measurement signals in the brain.

  If the electrode 2 is composed of more than two wires, at least one of these wires can act as the sensor 3. Consequently, in this case, there is an embodiment in which the electrode 2 and the sensor 3 are integrated in a single member. The wires of electrode 2 may have different lengths. As a result, these electrodes 2 can penetrate to different brain depths. When the electrode 2 is composed of n wires when n is an integer of 3 or more, stimulation can be performed by at least a pair of wires. Any sub-combination of wires is possible in pairs. Stimulation can also be realized between one of the n wires and the metal part of the generator housing. In addition to this member, there may also be a sensor 3 that is not structurally integrated with the electrode 2.

  Illustratively and specifically, neuronal activity is measured by the device of the present invention using a sensor in the first step. In a second step, the stimulation signal is generated by further processing the measured signal, for example by time delay of neuronal activity, possibly filtering and / or amplification. The stimulus generated from this stimulus signal is then used for stimulation in a third operating step through the implanted electrode. As a result of this stimulation, abnormal activity decoupling and / or asynchrony occurs in the stimulated tissue. Details of the operation of the apparatus of the present invention are described in Chapter 1.

  As noted in Chapter 6, the device of the present invention can be implemented in various embodiments of time control of stimulus application. These implementations of stimulus application time control are stimulus applications that are continuously repeated and demand controlled.

  The sustained stimulation application of the present invention is a simple embodiment of the device of the present invention. This embodiment operates without additional demand control and applies the stimulus continuously as described in Section 6.1. This continuous stimulation application thus represents an easily implemented embodiment of the device of the invention. At the same time, with a small energy input to the group of neurons to be decoupled or made asynchronous, the good decoupling and / or asynchronous effect of sustained stimulation is the need for autonomous control of the invention described in Chapter 5. Obtained due to control.

  In the repeated stimulus application of the present invention, the device of the present invention has a control system. The control system is programmed so that the control system applies a stimulus to the electrode 2 only for a specific period of time. Stimulation is not applied outside these periods. Therefore, in the repetitive stimulus implementation described in chapter 6.2, for example, the time period when the stimulus signal is calculated by the control device 2 relative to the time point determined by the control device 4, for example, following one after another. The control device 4 is programmed so as to be generated and output to the electrode 2. As in the case of continuous stimulus application, the demand control for autonomous control of the stimulus signal according to Chapter 5 is also performed by repeated stimulus application.

  With the demand-controlled stimulation application of the present invention, the device of the present invention has additional demand control as described in Chapter 6.3. For this reason, the device according to the invention preferably comprises means for detecting the occurrence and / or traces of abnormal features in the signal of the electrode 2 and / or in the sensor 3 and / or in the neuronal activity to be processed. In the demand-controlled stimulus application implementation described in Chapter 6.3, a stimulus signal is output to the electrode 2 in response to the occurrence and trace of abnormal features. As a result, brain tissue is stimulated. This causes abnormal neuronal activity within the neuron group to be decoupled and / or desynchronized, thus approaching normal physiological conditions. Abnormal activity is distinguished from healthy activity by a characteristic change in its pattern and / or its amplitude and / or its frequency component and / or its change over time. The means for detecting an abnormal pattern is a computer that processes the measurement signals of the electrode 2 and / or the sensor 3 and compares these measurement signals with data stored in the computer. The computer has a data medium for storing data. These data can be used within the scope of calibration and / or control according to Chapters 6 and 7. The control device 4 can be composed, for example, of a chip or other electronic device with comparable computing power.

  In the embodiment of the demand-controlled stimulation application described in chapter 6.3, the control device is such that the stimulation is generated at the stimulation interval predetermined by the control device 4 and output to the electrode 2. 4 is programmed. Overall, it relates to all parameters relating to the type and intensity of stimuli associated with the respective procedure of the device of the invention and to their time delay and the information applied to the electrodes and the functions to be controlled, the sensor 3 The measured values calculated by or parameters derived from these measured values are stored.

  The control device 4 controls the electrode 2 preferably in the following way: Control data is transferred from the control device 4 to the optical transmitter 5 for stimulation. The optical transmitter 5 controls the optical receiver 7 through the optical fiber 6. The control device 4 is electrically isolated from the electrode 2 by optically coupling the control signal to the optical receiver 7. This means that interference signals are prevented from entering the electrode 2 from the device 4 that processes and controls the signal. A possible optical receiver is, for example, a photocell. The optical receiver 7 transfers a signal input by the stimulation optical transmitter 5 to the stimulation device 8. The appropriate stimulus is then transferred by the stimulator 8 through the electrode 2 to the target area in the brain. If the measurement is also carried out through the electrode 2, the relay 9 is also activated from the stimulating optical transmitter 5 through the optical receiver 7. This optical transmitter 5 prevents an interference signal from entering. The relay 9 or transistor ensures that neuronal activity can be measured again immediately after each stimulus without over-exciting the isolation amplifier. Electrical isolation does not necessarily have to be implemented by optically coupling control signals, but rather other alternative control systems may be used. For example, these control systems may be acoustic connections in the ultrasonic band, for example. Control without interference can be achieved, for example, by using appropriate analog or digital filters.

  Furthermore, the device according to the invention is preferably connected via a telemetry receiver 12 to means 13 for displaying and processing measurement signals and / or stimulation signals and storing data. In this arrangement, the device 13 has a method for analyzing the data described below.

  Furthermore, in order to monitor the regular operation of the equipment and in some cases efficiently configure the control mechanism described in chapter 7.2 by changing parameters, the device of the present invention is Can be connected to an additional reference database via the telemetry receiver 13.

  Chapter 1 explains the mechanism of stimulation in detail. The definitions of the most important terms are given in Chapter 2. The operation steps from the measurement of neuronal activity through the generation of neuronal activity to the generation of stimulus signals are described in Chapter 3. The spatial arrangement of electrodes and sensors is described in Chapter 4. Chapter 5 explains request control for autonomous control of stimulus signals. Chapters 6 and 7 describe control of stimulus application and calibration and adaptation of stimulus parameters. In Chapter 8, examples and other possible applications and device implementations are described. The advantages of the device of the present invention are described in Chapter 9.

1 Mechanism of Stimulation The method and apparatus of the present invention can be used to decouple from moving neurons to moving neurons. The group of neurons in motion can also be made asynchronous. This relationship is shown in FIG.

  This is done by applying a stimulus with an electrode. These stimuli are generated by the neuronal activity being measured and converted and applied to stimulus signals and stimuli after processing steps that may also be present, especially including time delays. As a result, decoupling and / or asynchrony occurs significantly. As described in Chapter 3.1, the exercised neuron group 2 is stimulated by the decoupling process (FIG. 4). In asynchronous processing, the moving neuron group 1 is stimulated.

  By using the device of the present invention and the stimulation method of the present invention, the group of neurons to be decoupled is brought into a decoupled and unsynchronized state, or the group of neurons to be de-synchronized Is done. The desired state, ie complete decoupling and / or asynchrony, generally occurs during several cycles of neuronal activity, often less than one cycle. Neurons to be decoupled and / or desynchronized generally persist or repeat because after stimulation is interrupted, the experience is due to illness and / or to resynchronization due to coupling I need stimulation. Since stimulation is directly related to neuronal activity according to the present invention, the amplitude of the effect of the resulting stimulation, i.e. the sum of the coupling and stimulation for the group of neurons to be decoupled or made unsynchronized, and / or Minimized after asynchronous.

  This is made possible by using feedback stimulation signals, i.e. processed neuronal activity, as stimuli. That is, the degree of synchronization or coupling continuously controls the intensity and shape of the stimulus signal. The applied stimulus signal compensates for external coupling and / or internal synchronization. As a result, the amplitude of the stimulus effect that occurs on the group of neurons to be decoupled or made asynchronous is minimized. The neuronal activity of these neuron groups approaches a normal physiological state. This process operates on a large area of variable stimulation parameters such as stimulation period T, time delay and intensity, does not require expensive calibration and has large tolerances. Furthermore, due to the direct relationship between neuronal activity and the stimulation pattern, energy input into the tissue to be decoupled or made asynchronous is minimized. This predicts only a few side effects.

  In the following, the apparatus of the present invention and its functions are described by way of example.

  The apparatus and control system of the present invention are configured by means capable of executing all the steps of the processing method of the present invention.

Means for performing the method steps are also indirectly described by the described method steps. The method steps thus show the features of the device functioning simultaneously.
According to the invention, the electrode is implanted in the brain region or, in the case of an electroencephalogram electrode, attached to the brain region. Preferably, the brain region is selected such that the brain region is connected to or directly belongs to one or many brain regions that are the source of disease or are activated by abnormal activity Is done.

  In this case, this electrode outputs an electrical signal around it. This electrical signal causes decoupling and / or desynchronization directly in its peripheral region or in another region through the nerve fiber bundle. To cause decoupling and / or asynchrony, measured and processed, particularly time-delayed neuronal activity is used as a stimulus signal, see Chapter 3. Thus, the device of the present invention has a control system. The control system controls the electrode 2 so that the electrode 2 causes decoupling and / or desynchronization in another brain region by sending further stimulation in the nearby peripheral region and / or through the nerve fiber bundle. . In accordance with the present invention, the electrodes are controlled by stimuli generated from measured and processed neuronal activity that is delayed by an integer multiple of T / 2 in particular. T is the stimulation period and approximates to the period of rhythmic neuronal activity of an active or active group of neurons as described below. If the stimulation electrode 2 is not located in the region to be decoupled or desynchronized, the propagation time between the stimulation point and the point of the neuron group affected thereby is controlled when controlling such an electrode 2. It is necessary to consider. This is noted in Chapter 7.3. In the case of this stimulus, all the neurons to be decoupled are decoupled and made asynchronous and / or the neurons to be made asynchronous are made asynchronous. This simultaneously suppresses abnormal symptoms. If the electrode 2 is located outside the region to be decoupled and desynchronized, the effect of indirect stimulation needs to be taken into account as described in Chapter 7.3.

  By this novel method and this novel device, the object of suppressing abnormal symptoms is achieved as compared with the above-described conventional technique aiming at another method in nature. Rather than suppressing the neuronal activity of a group of neurons that synchronize abnormally with a strong stimulus, a group of neurons that act in synchrony with the anomaly can be easily made asynchronous or another Neurons are decoupled and made asynchronous by this action. This suppresses abnormal symptoms. The physiological activity of individual neurons is not affected. Neuronal activity processed according to chapter 3.3 is used at the stimulation point during this processing. Vigorous decoupling and / or asynchrony is assisted by interactions between neurons in the region of motion. A mechanism of action acting on abnormal synchronization is used. That is, the energy of the system to work on is used to obtain a therapeutic effect with minimal intervention. The best results are obtained when a stimulus is used that is generated from a stimulus signal whose time delay corresponds to an integral multiple of half the stimulus period T. The stimulation period T approximates the period of abnormal activity. However, if the time delay of the stimulation output by the electrode 2 includes another time delay, further treatment results are obtained. In this case, for example, at least some decoupling and / or asynchrony is obtained. The closer the selected time delay is to an integral multiple of half the period of abnormal activity, the better the treatment results.

Definition of 2 hours
Neuron activity:
The description of the mechanism of the device of the present invention is essentially based on the term neuronal activity. Neuronal activity of neurons to be decoupled and / or neurons to be desynchronized (see terminology of active and active neurons) is measured, stored, processed according to chapter 3.3, and feedback Used as a stimulus signal. As a result, the request control for autonomous control of the present invention is performed. In the following, the measured neuronal activity of the group of neurons to be decoupled and / or desynchronized is understood as a signal representing the temporal occurrence of the activity of the group of neurons to be decoupled and / or desynchronized. The For example, the local field potential can represent the temporal generation of activity of a group of neurons that should be decoupled and / or made asynchronous. Neuronal activity can preferably be measured directly in the region to be decoupled and / or desynchronized. However, it is related to the neuronal activity of the region to be decoupled and / or the region to be desynchronized, e.g. another brain region, e.g. It is also possible to measure the activity of the muscle groups to be controlled by the power region. In another embodiment of the device of the present invention, neuronal activity can be measured and combined at various locations to adequately represent the neuronal activity of the neurons to be decoupled and / or to be asynchronous. The quantity associated with neuronal activity in the region to be decoupled and / or in the region to be asynchronous is also referred to below as neuronal activity and is included in this term.

rhythm:
Rhythm is understood as rhythmic or almost periodic neuronal activity. This neuronal activity can occur as a result of activities that are overly synchronized to neuronal abnormalities. Rhythms can occur for a short period or for a long period of time.

period:
The main term for the device of the invention is the period of rhythmic neuronal activity. This period is used as a time reference for applying the stimulus. For example, by adapting the stimulation period T as described in section 7.2.1, the period of rhythmic neuronal activity preferably coincides with the stimulation period T.

Active neurons:
An active neuron group is understood as a neuron cell group that generates neuron activity that synchronizes to an abnormality or represents an activity that synchronizes to an abnormality in an associated region. The active neuron group transfers the activity synchronized to the abnormality to the active neuron (FIG. 4). An abnormal rhythm of an active neuron group (1) occurs under the involvement of almost all active neuron groups and / or (2) occurs within a part of an active neuron group and / or ( 3) Occurs in an active neuron group and a third neuron group different from the active neuron group. This third group of neurons activates the active group of neurons. In the case of (3), the active neuron group itself is the active neuron group. An active neuron is also called a group of neurons to be asynchronous or a region to be asynchronous. The active neuron population is not bound by the field of anatomy. Rather
-At least part of at least one field of anatomy,
-At least one complete anatomy field,
Can be interpreted as at least one element consisting of the following groups.

Activated neurons:
An activated group of neurons is understood as a group of neurons that are directly or indirectly affected through an active group of neurons (FIG. 4). A direct effect means an effect via a nerve fiber that connects two groups of neurons directly—that is, without an intermediate connection of another group of neurons. An indirect effect means an effect via at least one intermediately connected neuron. A group of neurons affected by an active group of neurons is also called a group of neurons to be decoupled or a region to be decoupled. The area to be decoupled is not bound by the field of anatomy. Rather
-At least part of at least one field of anatomy,
-At least one complete anatomy field,
Can be interpreted as at least one element consisting of the following groups.

  The region, the subthalamic nucleus-palm bulb outer segment junction, can be used as an example of a moving neuron group. This connection can act as a pacemaker due to illness and generate anomalous synchronized activity. The generated synchronous activity controls neuronal activity in the cerebrum, for example, the motor area. This motor area, which can be referred to here as a group of motorized neurons, is also connected to muscles and controls the activity of these muscles.

Decoupling stimulus:
Decoupling stimulation in the sense of the present invention minimizes this effect so that the abnormally active effect of the active neuron group on the active neuron group does not function, i.e. does not cause symptoms. It is understood as a stimulus to limit.

Target neuron group:
In the following specification, the target neuron group is understood as a neuron group that is directly stimulated by the implanted stimulation electrode. The target neuron group is stimulated directly by electrodes implanted in or near the neuron group. The group of neurons to be decoupled and / or made asynchronous can be stimulated directly or indirectly.

Direct stimulation:
In this case, the stimulation electrode 2 is placed directly in the region to be decoupled or in the region to be asynchronous. This electrode 2 affects the target neuron group located in the region to be decoupled or in the region to be asynchronous.

Indirect stimulation:
In this case, the region to be decoupled or the region to be asynchronous is not directly stimulated by the stimulation electrode 2. Instead, a target neuron group or nerve fiber bundle functionally connected near the region to be decoupled or to be desynchronized is stimulated by the electrode 2. In this process, the effect of stimulation on the region to be decoupled or unsynchronized is preferably brought about through anatomical connections. For indirect stimulation, the term target area is adopted as a superordinate concept for target neuron groups and nerve fiber bundles. The term target area is understood in the following as a group of neurons closely connected to the area to be decoupled or desynchronized directly stimulated by the implanted electrode 2 and the connected nerve fiber bundles.

Time delay:
A signal is transferred to the stimulation electrode 2 by the device of the invention. These signals may correspond to neuronal activity (= feedback stimulus signals) for earlier time points measured according to chapter 3.2 and possibly processed. This time shift, hereinafter referred to as time delay, represents an important stimulation parameter related to the stimulation period T. This stimulation period T coincides with the period of rhythmic neuronal activity.

Feedback stimulus signal:
A stimulus signal or stimulus signal is understood as a signal that indicates the neuronal activity measured and processed and is used as a basis for the stimulus. The processing steps are performed, for example, as described in Chapter 3.3. The stimulation signal consists of the neuronal activity to be processed and is used to stimulate the brain region to be decoupled or to be asynchronous. In order to generate a feedback stimulus signal, it is necessary to produce the measurement signal with different processing parameters (especially different time delays), possibly by several processing steps which are not related to each other. These measurement signals are calculated, for example, by addition and / or multiplication and / or division and / or subtraction and / or by other non-linear functions to generate the actual stimulus signal. Stimulation is generated from the feedback stimulation signal and then applied to the target neuron group by the electrode.

Resulting stimulus effects The effect of the resulting stimulus on the group of neurons to be decoupled or desynchronized is the sum and solution of external forces applied to the group of neurons to be decoupled and / or desynchronized. Is done. According to Chapter 3.1, in an embodiment of the device of the invention, the activated neuron group is decoupled from the active neuron group by direct stimulation or joint stimulation. In this case, the effect of the resulting stimulus on the group of neurons to be decoupled is the sum of the active acting force of the coupling between the stimulus signal and the active group of neurons. In another embodiment of the device of the present invention, the active neurons that are to be desynchronized are desynchronized by the stimulus. The only effect of the resulting stimulus on the group of neurons to be asynchronous is here the stimulus signal. Due to the autonomous control requirement control described in Chapter 5, the amplitude of the resulting stimulus effect on the neuron group to be decoupled or the neuron group to be decoupled may result in successful decoupling and / or asynchrony. Minimized automatically later.

3 stimulation methods and forms of stimulation
3.1 Decoupling and Asynchronous Methods A group of neurons that are abnormally synchronized in the brain region act on another group of neurons that follow by rhythmic activity as an active force. As a result, as schematically shown in FIG. 4, an interaction in the form of “active neuron group-active neuron group” is obtained between the neuron groups. If the acting force is strong enough, the activated neurons are also synchronized. This can cause abnormal symptoms. This occurs when a neuron that has moved in the same way as in the pre-motor area or motor area controls the muscle.

  As noted in Chapter 1, the purpose of the device of the present invention and the stimulation method of the present invention is to suppress abnormally synchronized neuronal activity as expected. In the decoupling stimulus mode, the activated neuron group 2 is decoupled from the active neuron group 1 and made asynchronous. Or, in the case of the stimulus mode to be asynchronous, the active neuron group 1 is made asynchronous for this purpose.

  In the decoupling stimulation mode, the activated neuron group 2 is stimulated directly or indirectly by the stimulation electrode according to chapters 3.4 and 4.1. This stimulus decouples the neuron group from the active neuron group 1. As a result, the neurons are made asynchronous.

  In the stimulation mode to be asynchronous, the active neuron group 1 is stimulated directly or indirectly by the stimulation electrode. Neuron group 1 is made asynchronous by this stimulus. As a result, the force acting on the neuron group 2 disappears. Neuron group 2 is also made asynchronous. As a result, abnormal symptoms are suppressed. If the neuron group 2 itself is synchronized, this neuron group 2 needs to be made asynchronous directly, like the active neuron group.

  According to Chapter 5, request control for autonomous control of a stimulus signal occurs in the two stimulus methods described above. In this case, the effect of the resulting stimulus on the stimulated neuron group is automatically minimized. According to Chapter 2, the effect of the resulting stimulus on a group of neurons activated in the decoupling stimulus mode is the sum of the stimulus signal and the acting force of the active group of neurons. In the asynchronous stimulus mode, the resulting stimulus effect on the active neurons is exclusively the effect of the stimulus signal.

  In the following, an embodiment of the device according to the invention, i.e. a stimulation mode for decoupling, will be described by way of example. In this case, the neuron group to be decoupled is decoupled from the active neuron group by direct or indirect stimulation. Other embodiments of the device of the present invention are described in Chapter 8.

3.2 Measurement of neuronal activity The time course of neuronal activity in the area to be decoupled and / or active can be measured directly and / or indirectly by the sensor 3. In indirect measurements, the time course of the activity of the muscle groups affected by the area to be decoupled and / or the active area and / or the neuron groups assigned to the area to be decoupled and / or the active area The time course of the activity is measured by at least one of the sensors 3. The sensor 3 (see FIG. 1) is installed in the brain and / or outside the brain. In the brain, these sensors 3 are positioned in the area to be decoupled and / or in the active area and / or in at least one other area operatively connected to these areas. Outside the brain, the sensor 3 is placed on a muscle that is placed on a part of the body involved in neuronal activity that synchronizes abnormally, eg trembling as an electrode. The measurement signal of the neuron activity of the neuron group, for example, the muscle activity (also called neuron activity, see Chapter 2) is processed and stored in the signal processor 4. Measurement, processing and storage can be performed continuously or at discrete time intervals. In discrete time intervals, the duration and / or discrete measurement intervals are determined by deterministic and / or probabilistic algorithms.

3.3 Processing of the neuron measurement signal The measurement signal stored in the signal processor 4 is then processed and used as a feedback stimulus signal. The following processing steps can be used:
1. The measured neuronal activity can be filtered. For example, neuronal activity can be bandpass filtered. In addition to disease-related activity, this filtering may be necessary if, for example, further disease-related activity from another group of neurons is measured by the sensor 3. Since activity related to illness generally occurs in a different frequency range than activity not related to illness, activity in the frequency domain related to illness is preferably detected in this case. This is realized, for example, by frequency analysis. Similarly, it is also necessary to perform wavelet analysis and / or Hilbert transform and / or filtering in the time domain.

  2. If the neuronal activity of a group of neurons to be decoupled and / or a group of neurons to be desynchronized is measured by a number of sensors 3, the measured neuron activity can be combined linearly and / or non-linearly. For example, the measured neuron signals may be multiplied, divided, added and / or subtracted from each other or themselves and / or transformed by other non-linear functions.

  3. The measured neuronal activity is time delayed. The time delay used for this is defined in chapter 3.4 and also takes into account the position of the stimulation electrode with respect to the group of neurons to be decoupled according to chapter 7.3. Furthermore, the time delay can be adapted during stimulation, preferably according to chapters 7.2.1 and 7.2.2.

  4). The measured neuronal activity is amplified. The measured neuronal activity is generally several orders of magnitude smaller than the stimulus amplitude that causes the stimulus effect according to experience. It is therefore necessary to perform amplification that can be accommodated by stimulation according to chapter 7.2.3.

  5. The measured neuronal activity is encoded in time. Since a signal with a high gradient has a great influence on the dynamic characteristics of the neuron, the measured neuronal activity is encoded in the form of a pulse train composed of a plurality of short rectangular pulses, for example a low-frequency pulse train or a high-frequency pulse train. Other encoding methods may be used to improve stimulation.

  6). The polarity of neuronal activity changes.

  7. Neuronal activity is converted linearly and / or non-linearly. This can be done, for example, by a Hilbert transform and / or a Fourier transform and / or a wavelet transform.

  8). The maximum amplitude of the stimulus signal is limited.

  9. The measured signal is converted so that a stimulus signal is generated with a net charge input of approximately zero.

  10. The measured neuronal activity is used directly as a feedback stimulus signal.

  The processed neuronal activity or feedback stimulus signal is calculated by using at least one element of the processing steps described above. For example, stimulation signals can always be generated from measured neuronal activity using the same processing steps. A set of processing steps and / or their parameters are also changed in time by a deterministic algorithm and / or a stochastic algorithm and / or an algorithm that combines a deterministic algorithm and a stochastic algorithm. obtain.

3.4 Stimulus Morphology Stimulation is understood as stimulation applied by electrode 2 and acting within one time interval. To create a stimulus, a feedback stimulus signal, ie neuronal activity processed according to Chapter 3.3, is used. To generate the stimulus, the stimulus signals can be multiplied, divided, added and / or subtracted from each other or themselves and / or transformed by other non-linear functions. The time delay used during the processing of the neuronal activity is given, for example, as part of a period of neuronal activity to be oscillated decoupled and / or active, and is preferably primarily 1 / Nth of the period. Is a multiple. In this case, N is a small integer, for example 2. The time delay of the stimulation signal may be selected to be greater than the stimulation period T. The device of the present invention also offers the possibility to use a number of preferably different time delays for creating the stimulus. The resulting time delayed feedback stimulus signal is combined linearly and / or non-linearly to create a stimulus.

  For this reason, the device of the present invention comprises means for applying electrical stimulation in the manner described. This means is the control system 4 which sends to the electrode 2 a control signal for outputting the electrode 2 and these stimuli. Further, a sensor 3 and a signal processing device 4 are provided. This signal processor 4 receives neuronal activity and prepares this neuronal activity for further use as a stimulus. The stimulus is preferably generated and its total charge input is approximately zero.

  For example, the electrode 2 can be controlled by the same stimulus in the form of neuronal activity that has been treated in accordance with chapter 3.3. The electrode 2 may be controlled by different stimulation signals and / or combinations of stimulation signals and / or by different transformations and / or combinations of stimulation signals.

  The order and / or type and / or energy input and / or stimulation parameters can be determined by a deterministic algorithm and / or a stochastic algorithm and / or an algorithm that combines a deterministic algorithm and a stochastic algorithm. Can be determined. The time delay of use and / or polarity and / or the application period and / or the intensity of the stimuli used in the processing steps, see chapter 3.3, are systematically or randomly, ie deterministic rules or probability theory. Can be controlled according to general rules. For this reason, the device of the present invention has a control system. The control system is programmed such that it controls the time delay and / or polarity and / or application period and / or intensity of the stimulation processing steps deterministically and / or stochastically.

  By changing the time delay and / or polarity and / or duration of application and / or intensity within the processing step of the stimulation signal, an adaptation process within the neuron group that increases the stimulation intensity to obtain the same therapeutic effect may be prevented. .

4. Spatial arrangement of 4 electrodes and sensors 4.1 Stimulation electrode Preferably the electrode 2 is used for stimulation. If electrode 2 is positioned in a group of neurons to be decoupled, this electrode must be preferably arranged so that the electrode can be used to stimulate all the groups of neurons to be decoupled. Don't be. This can be achieved by geometrically positioning the electrodes. For example, the electrode 2 can be positioned in the center of the region to be decoupled.

  If the electrode 2 is not positioned in the group of neurons to be decoupled, in this form of stimulation, the stimulation is applied in a target area that is different from the area to be decoupled. At this time, indirect stimulation can be applied by stimulating a group of neurons different from the group of neurons to be decoupled and / or by stimulating a nerve fiber bundle that is connected to the group of neurons to be decoupled.

4.2 Number of Sensors The mechanism of the device of the present invention is that the measured and processed neuronal activity of the neuron group to be decoupled and / or the activated neuron group, as described in chapters 1 and 3, Essentially configured to be reapplied as a stimulus. The sensor 3 is the most important element of the device according to the invention and is outside the group of neurons to be decoupled and active, or preferably in the group of neurons to be decoupled and / or in the group of active neurons. Can be positioned directly. Only one sensor 3 is preferably used to detect the activity of the neurons to be decoupled and the active neurons. As a result, the number of sensors to be implanted is kept as low as possible to prevent unwanted tissue damage during implantation, particularly brain bleeding. In order to be able to more fully reproduce the neuronal activity of the group of neurons to be decoupled and / or the group of active neurons, for example, two or three sensors may be used. .

  Furthermore, the at least one sensor 3 and the stimulation electrode 2 are combined and united with one electrode to be implanted, thereby further reducing or preventing brain damage that may occur due to implantation. The effect is improved.

  If all the sensors 3 are positioned in the neuron group to be decoupled and / or the active neuron group, the majority of the neuron group to be decoupled and / or the active neuron group These sensors 3 should preferably be arranged so that a part can be detected by these sensors. This can be achieved by a sensor geometry that takes into account the tissue to be decoupled and / or the active tissue. When only one sensor 3 is arranged, this sensor 3 can be installed at the center of the tissue, for example. When arranging a large number of sensors, these sensors can be arranged symmetrically, for example.

  In this form of activity measurement, at least one sensor 3 is not positioned in the group of neurons to be decoupled and / or in the group of neurons that are active, in this form of activity measurement the group of neurons to be decoupled and / or active. The activity associated with the neuronal activity of a group of neurons is measured in at least one region different from the region to be decoupled and the active region. As noted in chapter 3.2, indirect measurements may be performed on different neuronal groups to be decoupled and / or different from active neuronal groups and / or neuronal groups to be decoupled and / or It can be performed by measuring the activity of nerve fiber bundles and / or parts of the body that are connected to active nerve cell populations.

5 Request Control for Autonomous Control of Stimulus Signal One of the most important features of the mechanism of the apparatus of the present invention is request control for autonomous control of the stimulus signal.

  The described autonomous control is implemented due to the fact that the stimulus consists of neuronal activity that is processed. In the case of stronger synchronizing activity in the region to be decoupled and / or in the case of coupling to the active neuron in the region to be decoupled, as known to those skilled in the art, A big change can be expected. This directly leads to a time delayed stimulus according to the present invention with increased stimulus amplitude. The force of the applied stimulus signal compensates according to the invention, ie the force of internal synchronization and / or the coupling force with active neurons in the region to be decoupled. As a result, the group of neurons to be decoupled is decoupled and made asynchronous. This uniquely minimizes the effect of the resulting stimulus on the group of neurons to be decoupled, ie the sum of the stimulus and the coupling. Slightly altered neuronal activity is expected after decoupling and asynchrony. As a result, the stimulus signal is directly affected and adapted independently. When a new coupling and / or resynchronization occurs again, a greater change in neuronal activity creates a stronger stimulus, thereby allowing the device of the present invention to increase the demand for decoupling and / or desynchronization. Will be considered automatically. This represents request control for autonomous control of the device of the present invention.

  A mechanism based on request control for autonomous control is effective in all embodiments of the device of the present invention, which will be described in detail below.

6 Stimulation Application Control Stimulation application time control is understood as an embodiment of the device of the invention, which is preferably pre-programmed. Stimulation is applied by the stimulator 8 in a specific way. The change in the time control of the stimulus application is a stimulus application according to the need to be repeated continuously. In addition, manual demand control can be performed for stimulus application performed, for example, by a patient or doctor.

6.1 Sustained stimulus application For sustained stimulus application, the device of the present invention has a control system. The control system is programmed so that the control system applies the stimulus continuously at the electrode 2. Sustained stimulus application represents the simplest and most easily implemented embodiment of the device of the present invention. At the same time, in spite of the autonomous control requirements control of the present invention described in Chapter 5, sustained stimulation is a good decoupling and asynchronous effect with less energy input into the neurons to be decoupled. I will provide a.

  Intensity parameters can be adapted according to chapter 7.2.3 during continuous stimulation application. Similarly, the time parameter—stimulus period T and / or time delay—is combined with or related to the adaptation of the stimulus intensity according to chapters 7.2.1 and 7.2.2 during sustained stimulation. Can be adapted without any problems.

6.2 Repeated stimulus application For repeated stimulus application, the device of the present invention has a control system. The control system is programmed so that the control system applies a stimulus at electrode 2 only during a specific time interval. The stimulus is not other than these time intervals. With repetitive stimulation, the stimulation can be applied periodically periodically in time or aperiodically in time. In this embodiment, the device of the present invention has a control system. The control system is programmed so that the control system controls the time intervals and / or periods between stimulation intervals periodically and / or aperiodically. In order to achieve the desired decoupled and desynchronized state of the group of neurons to be decoupled, a temporally non-periodic sequence of stimuli is deterministic and / or stochastic algorithm and / or decision It can be generated by an algorithm that combines a theoretical algorithm and a stochastic algorithm. Similarly, in the following, the combination of deterministic rules and probabilistic rules is understood as a functional relationship. In this relationship, deterministic terms and probabilistic terms are functionally connected to each other, for example, by addition and / or multiplication.

  Stimulation intervals and measurement intervals can be placed one on top of the other or simultaneously or separated in time. Intensity parameters can be adapted according to chapter 7.2.3 during repeated stimulation application. Similarly, the time parameter—stimulation period T and / or time delay—is combined with or in combination with stimulation intensity adaptation according to chapters 7.2.1 and 7.2.2 between repeated stimuli. Can be adapted independently.

6.3 Stimulus application controlled on demand In the case of demand controlled stimulation application, the device of the present invention has a control system. The control system is programmed in such a way that the on / off switching of the stimulus is performed according to the specific state of the neuron group to be decoupled and / or the active neuron group. For this reason, the control device 4 uses a measurement signal and / or a stimulation signal for detecting an abnormal feature. The stimulus is switched on, for example as described below.

The activity of the neurons to be decoupled and / or active neurons is measured by the sensor 3. This device 4 in which the neuronal activity is transferred to the device 4 for processing and / or controlling the signal, serves in particular as a means for detecting abnormal features. Immediately after the device 4 for processing and / or controlling the signal detects an abnormal feature in the neuronal activity, the application of the stimulus is started. Immediately after the abnormal feature disappears due to the effect of the stimulus application, the stimulus is preferably switched off. The device of the invention therefore comprises a computer as device 4 for processing and / or controlling / conditioning the signal in a possible embodiment. The computer has a data medium. The data medium stores disease pattern data and compares this data with measurement data. Disease pattern data includes parameters and measurements related to the stimulus, such as the instantaneous frequency of neuronal activity measured by the sensor 3, the threshold required for the controlled method of applying the stimulus, and the stimulus that defines the strength of the stimulus. It is interpreted as a parameter. Abnormal features may be interpreted as, for example, synchronization associated with disease of the neurons to be decoupled and / or active neurons and may be recognized by the following features of neuronal activity:
a) Abnormal activity in the group of neurons to be exclusively and / or decoupled and / or in the active group of neurons, eg directly stimulated as described in chapters 3.2 and 4.2 When measured by the sensor 3, the neuronal activity is directly used to check whether the amplitude of the neuronal activity has exceeded a threshold. In a preferred embodiment, the device of the invention is therefore equipped with means for detecting the value of the amplitude of neuronal activity corresponding to the threshold value. In this case, the neuronal activity itself and / or its value and / or its amplitude is preferably compared to a threshold value. In this embodiment, the means are programmed such that the means for detecting the threshold compares, for example, the neuronal activity itself and / or its value and / or its amplitude to the threshold. The amplitude is determined in a simple form by calculating the value of the signal and / or by band-pass filtering and / or by Hilbert transform and / or by wavelet analysis. In this case, the device 4 for processing this signal is programmed so that the device 4 for processing the signal can perform the calculation of the value of the signal and / or the bandpass filtering and / or the Hilbert transform and / or the wavelet analysis. . Amplitude calculations clearly represent a higher computational cost, and amplitude calculations can be performed on individual measurements of neuronal activity rather than within sufficiently large time intervals known to those skilled in the art. Neuronal activity or its value is particularly preferably used because it needs to be done. This can slightly delay the recognition of abnormal features.

  b) In addition to this abnormal activity of the group of neurons to be decoupled and / or the group of active neurons, for example as in the indirect measurements described in chapters 3.2 and 4.2, If non-disease-specific activity is additionally measured by the sensor 3, for example from other neuronal activity, further algorithm steps need to be inserted into the analysis of neuronal activity. Since disease-specific activity generally occurs in a different frequency range than activity that is not disease-specific, it is sufficient to preferably evaluate activity within the frequency specific to the disease for this purpose. The frequency of disease-specific activity is calculated, for example, by calculating the difference between successive trigger points. Trigger points are points such as maximum values, minimum values, branch points and zero-pass points. This analysis is preferably performed within a moving time window. An average of a number of time differences is generated. This average value improves the stability. Alternatively, the frequency may be estimated by spectral evaluation methods known to those skilled in the art and other frequency evaluations such as by Fourier transforms. In contrast, the device of the present invention comprises means for evaluating activity within a frequency range specific to the disease, such as spectral evaluation methods, Fourier analysis and / or wavelet analysis, in a special embodiment. This is performed, for example, by means of performing frequency analysis. For example, spectral energy within the frequency range inherent in the disease can be calculated within the moving window. Instead, the amplitude within the frequency inherent in the disease is determined by calculating the maximum value of the bandpass filtered signal after bandpass filtering or by calculating the average of the values of the bandpass filtered signal and It may be calculated by / or Hilbert transform and / or by wavelet transform. For this purpose, the device according to the invention comprises, for example, means for band-pass filtering the amplitude and means for calculating the maximum value of the band-pass filtered signal and / or means for calculating the average value of the band-pass filtered signal and / or Means for performing Hilbert transform and / or Hilbert transform and / or wavelet analysis.

  In a demand-controlled stimulus application, for example, the same stimulus is always used. The stimulation period T is preferably adapted to the instantaneous frequency of the group of neurons to be decoupled and / or the group of active neurons as described in section 7.2.1. If abnormal features are present, a stimulus having a stimulus period T adapted to the instantaneous frequency is applied. Similarly, the time delay can be adapted according to section 7.2.2 and / or the intensity of the stimulus is preferably kept constant. However, the intensity parameter may be changed according to the stimulating effect as in chapter 7.2.3.

6.3.1 Confirmation of requirements For at least two reasons, there is no unambiguous relationship between the appearance of abnormal features and the appearance of symptoms specific to the disease. On the one hand, if the sensor 3 is far away from the region to be decoupled and / or the region where the neuronal activity to be measured is generated, the amplitude in the frequency region specific to the disease changes. On the other hand, the specific appearance of disease-specific features, ie the appearance of rhythmic activity in the frequency domain specific to the disease, is not uniquely related to the disease-specific symptoms. Disease-specific rhythms more generally act on complex neuronal networks in the brain that do not follow simple linear dynamic rules, so there is a distinction between disease-specific rhythms and the appearance of symptoms. There is no relationship. For example, if the rhythm inherent to the disease does not sufficiently match the natural frequency of the limbs provided for biomechanics, the tremor caused by the rhythm inherent to the disease will resonate with the rhythm inherent to the disease and biomechanics It is clearly smaller than when it corresponds to the natural frequency of the limb that is provided.

  Characteristics of the measured neuronal activity, such as fundamental frequency and amplitude, are within a range known to those skilled in the art. The value of the appearance of a characteristic characteristic of the neuronal activity disease measured by the sensor 3 is called the threshold value. If this threshold is exceeded, symptoms typically occur, such as tremor. This threshold is a parameter that needs to be selected for the demand-controlled stimulus application implementation described in Section 6.3. The device according to the invention is therefore constituted by means for detecting a threshold value in the form of the control device 4. The inventive method of demand-controlled stimulus application provides the advantage that the effect of the invention is not critically dependent on the selection of the threshold, but that a large tolerance is given for the selection of the threshold. This tolerance is, for example, in the range of 50% of the maximum case of disease-specific features. The selection of the threshold is measured by measuring neuronal activity through the sensor 3 during surgery or preferably on the first day after surgery, by measuring the emergence of disease-specific features and comparing the occurrence of symptoms with eg tremor intensity. It is determined.

  In a preferred implementation of demand-controlled stimulation, the threshold value is a typical value, for example the average value of a threshold population measured in a threshold patient. In a preferred implementation, the threshold selection is checked at approximately regular intervals, for example during half a year.

  In the stimulus implementations described in Sections 6.1 and 6.2, which are continuously repeated at the required controlled stimulus intensity, no threshold detection is required.

  The three stimulation methods described above can preferably be used in various combinations of the methods for adapting the stimulation parameters noted in chapter 7.2.

  All three stimulation methods generally have demand control that is inherently autonomous in accordance with the present invention. The direct dependence of the stimulus signal on the measured neuronal activity causes the demanding control to be autonomously controlled as described in Chapter 5. As a result, the energy input into the group of neurons to be decoupled is minimized. This requirement control for autonomous control works regardless of the realization of the additional requirement control described in Chapter 6.3 and the calibration and control as described in Chapter 7.

7 Calibration and adaptation of parameters In the following, it is assumed that the electrode 2 is in the group of neurons to be decoupled. If the electrodes are outside the group of neurons to be decoupled, they are considered separately at the end of this chapter. Calibration and adaptation can be performed on the following parameters of the apparatus of the present invention. For example: the frequency of the stimulus signal whose inverse is equivalent to the stimulus cycle, the time delay of the stimulus signal, and the intensity of the stimulus.

7.1 Stimulation parameters at the start of stimulation 7.1.1 Frequency, stimulation cycle Frequency selection without prior operation of the device: The frequency range of abnormal neuronal activity is determined by the person skilled in the art for each disease pattern (Elble RJ and Koller WC (1990): Tremor, John Hopkins University Press, Baltimore). An average value is obtained from this frequency domain. Alternatively, predicted frequency values related to age and gender may be used.

  In order for the device of the invention to work well, it is not necessary to match the initially preset frequency to the actual frequency of activity of the neuron group to be decoupled or of the active neuron group. is there. The control of the stimulation period T described in Chapter 7.2.1 works even when initial values are used that deviate significantly from the correct frequency. “Large deviation” means that the value may be very large by at least a factor of 10 or very small. Alternatively, it is therefore possible to preferably start with a frequency value that is generally in the frequency range known to the illness and the person skilled in the art. The frequency value for the onset of stimulation is also preferably obtained by tailoring individually for each patient. This evaluates the fundamental frequency of the group of neurons to be decoupled and / or active, for example by measuring neuronal activity providing stimuli and as described in chapter 6.3 Can be realized.

  Selection of the frequency by prior operation of the device: The starting value for the frequency is selected to be the average value of the frequency during the aforementioned operation of the device. In both cases, i.e. with and without operation of the device described above, the stimulation period T is calculated as the reciprocal of the starting value of the frequency.

7.1.2 Time Delay The time delay of the stimulation signal is preferably calculated after the initial calculation of the stimulation frequency or stimulation period T. The time delay is preferably selected as a fraction of the stimulation period T, for example T / 2. Preferably, a time delay may be selected that corresponds to a fraction of the stimulation period T and possibly exceeds the stimulation period T. The time delay adaptation described in section 7.2.2 will work even if the time delay adaptation described in section 7.2.2 is described above. In this case, at least some of the delay times of the feedback stimulation signals are different and / or exceed the stimulation period T. Stimuli are generated from these time delays.

7.1.3 Intensity The starting value of the stimulation parameter that determines the intensity of the stimulation (eg, the amplitude of the feedback stimulation signal) is determined according to experimental values known to those skilled in the art (eg, maximum amplitude 10V). The intensity control described in Chapter 7.2.3 works even when initial values are used that deviate significantly from the optimum intensity values. “Large deviation” means that the value is very large by at least a factor of 10 (preferably a maximum amplitude of 10V) or very small. Alternatively, it is also possible to start with an intensity value that is preferably in a range known to the person skilled in the art. In order to reduce the side effects of stimulation as much as possible, it is preferable to start the stimulation with a particularly small intensity value, for example a maximum amplitude of 0.5 V. If it is necessary to use a stronger stimulus signal, the intensity can be increased in small steps as noted in chapter 7.2.3.

  Thus, the starting values for frequency and intensity can be preset and are determined without particularly time consuming calibration.

7.2 Adaptation of stimulation parameters 7.2.1 Adaptation of stimulation period T In areas where neuronal activity is to be decoupled and / or is active and / or functionally connected to this area Measured. This neuronal activity is used as a stimulus signal after processing. For example, in the case of Parkinson's disease, in addition to direct measurements in the area to be decoupled and / or active by the sensor 3, activity in subsequent areas, for example in the premotor area, is also measured by the electroencephalogram sensor. The dominant average period is calculated within the length of the time window described below. For this reason, different algorithms can be used. For example, the stimulation period T can be adapted to the instantaneous period of the group of neurons to be decoupled and / or the group of active neurons. For example, the instantaneous period can be calculated as the time difference between two consecutive maximum values of measured neuronal activity. For example, the average frequency of neuronal activity can be evaluated first and the stimulation period T can be calculated as the reciprocal of the average frequency. If only disease-specific activity is not measured by sensor 3, for this type of frequency assessment, disease-specific activity must first be extracted by bandpass filtering the frequency domain specific to the disease. . Alternatively, for example, the frequency can be calculated by frequency evaluation as described in Chapter 6.3. The time window used for the evaluation of this frequency has a length that can be opened to the above values, for example 10000 periods of abnormal activity, in particular 1000 periods, particularly preferably 100 periods, or any other value It corresponds to.

7.2.2 Time Delay Adaptation As noted in chapters 3.4 and 7.1.2, the time delay of the stimulation signal is preferably selected as a fraction of the stimulation period T. The time delay can be fixed, for example, during stimulation, or preferably can be adapted to a stimulation cycle adapted according to chapter 7.2.1. The time delay of the stimulus signal is preferably deterministic and / or probabilistic during the stimulus so that optimal decoupling and / or asynchrony can be achieved by the effect of the slight resulting stimulus It is changed by an algorithm and / or an algorithm that combines a deterministic algorithm and a stochastic algorithm. For this purpose, the device according to the invention has means in the form of a control device 4. This control device 4 makes it possible to change the time delay of the stimulation signal during stimulation. Furthermore, the time delay can be varied not only within the stimulation period, for example, but also within a number of periods. In this case, the stimulus signal corresponds to the neuronal activity measured at a point earlier by several cycles.

7.2.3 Intensity adaptation The neuron group representing the activity of the neuron group to be decoupled and / or active is measured by the sensor 3. This neuronal activity is transferred to a device 4 that processes and / or controls the signal. The device 4 for processing and / or controlling this signal implements a stimulus that is sustained or repeated or demand-controlled according to Chapter 6. The intensity of the stimulus applied at each time point depends on the appearance of abnormal features within the neuronal activity. For this reason, the intensity of the stimulus can be preferably adapted. In this embodiment, the device has a control system. The control system is programmed so that the control system changes the amplitude of the measurement signal according to chapter 3.3 to control the intensity of the stimulus. The relationship between the intensity of the stimulus and the appearance of abnormal features can be controlled manually or automatically depending on the stimulus result. In a time window that is freely selectable, preferably of a certain length and ends within a certain time interval before each stimulus, the appearance of abnormal features is detected in the following way:
a) If the activity to be exclusively or mainly decoupled and / or active is measured by the sensor 3, the amplitude corresponds to the appearance of synchronization of the group of neurons to be decoupled. This amplitude thus represents an abnormal feature. In this case, the amplitude may be evaluated by calculating the maximum value of the signal or by the average value of the signal or by band-pass filtering and / or by Hilbert transform and / or wavelet analysis. Calculation of amplitudes by Hilbert transform and / or wavelet analysis clearly represents a higher computational cost, and the accuracy of these calculations depends on the correct choice of algorithmic parameters, so the first two methods (maximum signal The calculation of the value or the average value of the signal values) is particularly preferably used.

  b) In addition to disease-specific activity, neuronal activity cannot be used directly for the appearance of abnormal features, eg when non-disease-specific activity from another group of neurons is also measured. Since the disease specific activity generally occurs in a frequency range that is different from the frequency of the non-disease activity, the activity assessment is preferably carried out in this case in the frequency range specific to the disease. This is realized, for example, by frequency analysis. For example, the spectral energy in the frequency domain specific to the disease can be calculated. Instead, the amplitude is determined by calculating the maximum value of the bandpass filtered signal after bandpass filtering or by calculating the mean value of the signal values and / or by Hilbert transform and / or by wavelet analysis. Can be done.

  If the desired effect is not achieved, i.e. the group of neurons to be decoupled is not sufficiently decoupled, and therefore the abnormal characteristics of neuronal activity do not move below the threshold, the maximum intensity of stimulation is safe. For a reason, it is gradually increased to a preset maximum value, for example, 5 V (for example, in a step of 0.5 V per 50 cycles). In contrast, the device of the present invention has a control system. This control system recognizes changes in neuronal activity and adapts the stimulus signal to the above values upon loss of conversion of neuronal activity. As long as the effect of the stimulus still exists, the device gently controls the maximum intensity of the stimulus downward (eg, in steps of 0.5 V per 50 cycles) after about 20 cycles without the problem of stimulation. The effect of stimulation is calculated as described above. The control system is programmed so that it recognizes changes in neuronal activity and the effects of stimulation. The maximum stimulus intensity is preferably controlled on a time scale between 10 and 1000 of neuronal activity so that the group of neurons to be decoupled is fully decoupled and desynchronized. Regardless of the value of the stimulus intensity described above, the amplitude of the resulting stimulus effect on the group of neurons to be decoupled is attributed to the characteristics of the stimulus mechanism of the device of the present invention described in Chapter 5. Automatically after decoupling without problems.

7.3 Stimulus parameters when the electrode is not in the neuron group to be decoupled As described for the electrode 2 not installed in the neuron group 2 to be decoupled, the neuron group to be decoupled is Affected by indirect stimuli as described in section 4.1. In the case of indirect stimulation, the transmission time between one stimulated target neuron group and the other neuron group to be decoupled can be different in each case, so before the decoupling stimulation is performed. First, each transmission time is measured first. For this purpose, a stimulus is applied through the stimulation electrode 2 and the response to this stimulation is measured through a sensor 3 installed in the group of neurons to be decoupled. This is done L times. In this case, L is generally a small integer up to 200, for example. The average transmission time is now evaluated in particular in the following way:
The period between the start of the application of the stimulus through the electrode 2 and the first maximum value of the response to this stimulus or the value of the response to this stimulus τ ^(k) is calculated for each stimulus application Is done. The index k of τ ^(k) indicates the kth applied stimulus. From this, the average period between the start of the stimulus and the response of the stimulus is calculated separately for the stimulation electrode 2. Stimulation is applied indirectly through the stimulation electrode 2 according to Equation 1 below.

  In this case, L is the number of stimuli applied through the stimulation electrode 2.

For stimulation, the average of the transmission time τ measured in this way is considered in the following way:
When stimulating a group of neurons to be decoupled directly through the stimulation electrode 2, when the stimulation is applied with a time delay t, the stimulation is time delayed t- (mean value of τ) when indirectly stimulated through the stimulation electrode 2. Given in. In this case, t needs to be larger than the average value of τ. This can be achieved according to section 7.2.2.

  The stimulus parameters at the start of the stimulus and the stimulus mechanism between the stimuli are exactly the same as described in chapters 7.1 and 7.2 under the above considerations of transmission time (mean of τ) It is determined.

8 Device examples and other implementations
8.1 Examples The following stimuli can be output through the electrodes:
1. A stimulus is applied through the electrode: this stimulus consists of two components: a feedback stimulus signal, ie processed neuronal activity. In this case, the stimulus signals are shifted by T / 2 in time. In this case, T is the average period of oscillation of the group of neurons to be decoupled. The neuronal activity processed without time delay is added to this signal. In general, this activity forms a stimulus, see FIG.

  2. A signal is applied through the electrodes: this signal consists of three components: the neuronal activity that has been processed and not time-delayed is squared and multiplied by the neuronal activity that has been time-delayed by T / 2 and processed. In this case, T is the rhythm cycle of the active neuron group. The effect of stimulation on the group of neurons to be decoupled appears as a decrease in the amplitude of the measured neuronal activity, FIGS. 2a and 3a. In this case, the firing pattern of the neuron is clearly different from the firing pattern of the abnormal state, see FIGS. 2b and 3b. The effect of this stimulus also appears in the degree of synchronization of the group of neurons to be decoupled, see FIGS. 2c and 3c. This is an asynchronous confirmation of the group of neurons to be decoupled. In this process, the resulting stimulus effect, ie, the combined amplitude of the stimulus and the stimulus, is automatically reduced due to the demand control for the autonomous control of the stimulus signal described in Chapter 5. See FIGS. 2d and 3d. Furthermore, the influence of the intrinsic dynamic properties of neurons does not occur during stimulation. This confirms that the natural frequencies of the neurons are dispersed in FIGS. 2e and 3e. The natural frequency is taken as the frequency of the neuron in the absence of interaction and no stimulation. This confirms that optimal decoupling and asynchrony of the neuron group to be decoupled occurs due to the stimulation of the present invention, and thus the neuron group returns to its normal functional state. This allows for the expected considerable reduction of disease related symptoms.

For example, three different control mechanisms of stimulus application, as described in Chapter 6, are used for stimuli. This allows gentle stimulation, preferably as described in Chapter 7, which saves demand control and saves energy (avoids side effects):
1. Sustained stimulus application: Stimulation is applied continuously, preferably with a matched stimulation cycle. Decoupling and desynchronization of the neurons to be decoupled occurs immediately after the application of the stimulus. This minimizes the amplitude of the measured neuronal activity. At the same time, the resulting amplitude of influence on the group of neurons to be decoupled is minimized due to the autonomously demanding control mechanism described in Chapter 5. After the stimulus is switched off, resynchronization occurs after a short period due to an abnormal interaction between the neuron groups.

  2. In particular, repeated stimulus application depending on the intensity of the stimulus to be controlled: The stimulus is repeatedly applied. In this process, the strength of the stimulus is adapted to the strength of synchronization of the neuron group: the stronger the coupling and / or synchronization, the stronger the adapted stimulus.

  In this embodiment, preferably τ / 2 can be selected as a time delay instead of T / 2. In this case, T is the period of rhythm without stimulation. τ is a period forced to rhythm by a stimulus. In other words: 1 / τ is the frequency of the stimulus signal. Individual signals are applied at this frequency. As a result, only important stimulation parameters are input to the system: instead of properly determining this stimulation parameter within the scope of expensive calibration, this stimulation parameter is determined by the stimulation. Furthermore, for this form of demand-controlled stimulation, a situation is used in which neurons in the affected area tend to fire or burst (abnormally) (occurrence of a burst of action potential bursts). . Therefore, tuning of the neuronal activity of the group of neurons to be decoupled can be realized with respect to the forced frequency.

  3. Stimulus demand controlled stimulus application (ie demand controlled selection of stimulus disclosure time and end time): If the synchronization of a neuron population exceeds a threshold, the next stimulus is in Chapter 6.3. Is output through the electrodes as described in.

  For all three control methods exemplarily described above, the autonomous control request control described in Chapter 5 minimizes the energy input into the group of neurons to be decoupled. In this process, very important stimulation parameters, stimulation period T and time delay are connected in the vicinity of the neurons to be decoupled and / or the neurons in the active neurons or close to these neurons. It can be preferably adapted by measuring the frequency of another group of neurons.

  For example, multiple stimulation contacts may be positioned at different distances from the ends of the electrodes, thereby integrating multiple stimulation electrodes into a single stimulation electrode to be implanted. This makes it possible to achieve stimulation of the area to be decoupled as wide as possible.

8.2 Other Embodiments of the Device The device of the present invention can also be used to asynchronously synchronize groups of neurons that are abnormally synchronized. In this embodiment of the device according to the invention, abnormally synchronized groups of neurons, for example active neurones to be made asynchronous, are made asynchronous by means of stimulation with the feedback stimulus signal according to the invention. The above mentioned characteristics of the device and the stimulation method for decoupling the group of neurons to be decoupled are also used for this embodiment of the device with the changes applied in the neuron where the stimulation is to be asynchronous.

  In the case of trying to be asynchronous, this can be achieved by placing the stimulation electrode 2 according to Chapter 4.1. Similarly, direct or indirect placement of the sensor 3 is possible. In this case, it is necessary to arrange the sensor 3 so that the neuron activity in the region to be asynchronous can be detected. The details of this arrangement are consistent with the details described in Chapter 4.2. In this case, the activity to be asynchronous is measured. The activity synchronized to the abnormalities of the group of neurons to be asynchronous is measured and processed directly and / or indirectly according to Chapter 3. This generates a stimulus signal that is used as a reference for the stimulus. The generated stimulus is applied to the region to be made asynchronous by the stimulation electrode. As a result, the group of neurons to be desynchronized is stimulated directly or indirectly according to chapters 3 and 4.1, the group of active neurons is desynchronized according to the present invention, and abnormal symptoms are suppressed. If the active coupling to an active neuron group is automatically decoupled due to the asynchronousness of the active neuron group, ie, the asynchronous of the active neuron group, Abnormal activity disappears. Due to the relationship between the stimulus signal and the neuronal activity of the neuron group to be asynchronous, the amplitude of the effect resulting from the stimulus to the neuron group to be asynchronous, ie the amplitude of the stimulus signal in this case (see Chapter 2) Is minimized as described in Chapter 5.

  The arrangement of electrodes and sensors adapted to the purpose of stimulation according to Chapter 4, all three control methods for controlling the application of stimulation according to Chapter 6 and the calibration and adaptation of parameters according to Chapter 7 are described in the book It can also be used for embodiments of the inventive device.

  This device can also be used to decouple a group of neurons that are active by an asynchronous, abnormal group of neurons. Furthermore, the device can be used to decouple a group of neurons that are activated by abnormal activity and, when decoupled, have activity that normally synchronizes itself. In this case, the arrangement of electrodes and sensors is equal to the arrangement described in Chapter 4. Detection and processing of neuronal activity is also performed according to Chapter 3.

  In addition, the device can be used to remove or suppress normal area coupling. This can be used, for example, in testing neuronal group interactions. In this case, the detection and processing of neuronal activity and the arrangement of electrodes and sensors are realized according to Chapters 3 and 4.

  As explained at the outset, if bilateral stimulation is necessary to decouple abnormal activity, the stimulation will at least produce a plurality of signals designed by two separate devices or for this purpose. Preferably applied bilaterally by one device of the present invention that transfers to two stimulation electrodes.

9 Advantages The device of the present invention has many advantages over existing devices, for example, German Patent Application No. 103 18 071.0-33 “Device for Asynchronizing Brain Neuronal Activity”:
1. The main advantage of the device according to the invention is that a physiological stimulus, ie a feedback stimulus signal, ie the measured and processed neuronal activity of the group of neurons to be decoupled and / or the group of neurons to be asynchronous is used for the stimulus. It is a point to be done. As a result, the request control for autonomously controlling the stimulus signal described in Chapter 5 is performed. This demand control minimizes the energy input into the group of neurons to be decoupled and / or the group of neurons to be asynchronous and has few side effects.

  2. Since energy-saving signals are used for stimuli due to demand-controlled stimulus signals, and energy savings can be expected with the control device of the invention required for stimulus control, The device operates with energy savings due to the autonomously controlled stimulus signal according to Chapter 5. As a result, the required battery replacement interval that tires the patient can be made longer.

  3. Since there is no need to detect a threshold in this method, a repetitive or sustained application implementation with a controlled stimulus intensity is particularly effective. As a result, this embodiment can be implemented by means of simpler algorithms. Therefore, the software or hardware of these algorithms is not complicated at all.

  4). For persistent and repetitive stimuli due to the direct stimulation of the intensity of the required controlled stimulus and the neuronal activity to be decoupled or desynchronized, no calibration is necessary. That is, there is no need to perform a series of test stimuli in which the stimulus parameters are systematically changed. This shortens the calibration period.

  5. Compared to the evaluation of parameters such as intensity, stimulation period and time delay, the general tolerances and robustness of the device of the present invention are a major advantage overall.

  6). The complexity of the surgery, and therefore the complexity during the surgery, is significantly reduced for the patient by using only one electrode. As a result, the device of the present invention provides a gentler stimulus application.

  7. The area to be decoupled is preferably located close to the surface of the brain, for example in the motor cortex, so that access to the area to be stimulated is easier, without risk, for example without deep implantation of the stimulation electrode Realized.

  8). The device can also be used to decouple normal activity, thus providing a new and important possibility for testing the interaction of groups of neurons in the brain.

The lack of time-consuming calibration and the stability of the action during stronger frequency fluctuations-especially in Method 1 for controlling the stimulation application (sustained stimulation, see Chapter 6.1)-have important consequences:
1. Stimulation results can be checked quickly even during surgery while changing electrodes. As a result, finding a suitable target point can be clearly improved. Conventional demand-controlled methods require calibration that lasts more than 30 minutes per electrode. This calibration cannot be performed during surgery (without anesthesia) and is very burdensome for the patient.

  2. Novel stimulation methods can also be used in neurological or mental illnesses. In this disease, the abnormal rhythm has a frequency that varies greatly. In particular, these methods can also be used to decouple rhythms that occur intermittently (ie, short periods). As a result, these stimulation methods can be used with more diseases, especially in the case of epilepsy.

  Using the device of the present invention, the following diseases or conditions can be treated by a novel method of decoupling the appropriate brain region.

  Any neurological or mental illness: eg Parkinson's disease, essential tremor, ataxia, obsessive compulsive disorder, tremor in multiple sclerosis, tremor resulting from seizures or other tumorous tissue, eg thalamus and / or cerebrum In tremors, dance athetosis and epilepsy resulting from injury in the basal ganglia region, abnormal neuronal synchronization is associated with the appearance of disease-specific symptoms. This list of diseases is not limiting.

The standard method currently used for high frequency sustained stimulation uses the following target areas: For example:
The hypothalamic nucleus in the case of Parkinson's disease, or the thalamus in the case of Parkinson's disease where tremor is predominant, for example, the thalamic mid ventral nucleus

  In the case of essential tremor, the thalamus, for example the thalamic mid ventral nucleus.

  In the case of schizophrenia and choreoathetosis, the inner section of the dansyu. In the case of hemorrhoids, the pallidum bulb, cerebellum, thalamic core region, such as the thalamic mid ventral nucleus or caudate nucleus.

  In the case of obsessive-compulsive disorder, encapsulated or immediate nucleus

  In the device of the present invention, for example, the target areas listed above for each disease and / or areas connected to these areas can be selected. In the case of the device according to the invention, no further calibration is necessary or the calibration can be performed very quickly, so that another target area in which the decoupling and / or asynchronous action of the device according to the invention is further improved during electrode implantation. Can be tested.

  The present invention also relates to a control system for controlling the given functions of the device of the present invention and the use of the device and diseases such as Parkinson's disease, essential tremor, ataxia, obsessive compulsive disorder, butoh athetosis, multiple sclerosis Control systems to treat tremors, tremors resulting from seizures, or other tumorous tissues, such as tremors resulting from injury within the thalamus and / or basal ganglia region, and epilepsy.

  The device of the present invention is used for implantation and diagnosis of a target point during surgery for the continuous treatment of the above-mentioned neurological and mental illnesses, that is, for finding an optimal target point for implantation of an electrode during surgery. obtain.

1 shows an apparatus of the present invention. 8 shows the decoupling effect of a stimulus by a stimulus as described in Example 1 of Chapter 8.1. 8 shows the decoupling effect of a stimulus by a stimulus as described in Example 2 of Chapter 8.1. FIG. 2 is a schematic diagram of the coupling between a neuron group 1 synchronized with an active abnormality and a neuron group 2 to be decoupled that is active.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Insulation amplifier 2 Electrode 3 Sensor 4 Control apparatus 5 Optical transmitter 6 Optical fiber 7 Optical receiver 8 Stimulator 9 Relay 10 Conductor 11 Telemetry transmitter 12 Telemetry receiver 13 Means for displaying, processing and storing data

Claims (82)

In a device that decouples and / or desynchronizes brain neuronal activity, the device comprises:
-Having at least one sensor (3) measuring at least one signal that reproduces the time course of the activity of the neurons to be decoupled and / or to be asynchronous;
-With one electrode (2) and-with a control system (4), which receives the measurement signals of the sensor (3) and derives stimulation signals and stimuli from these signals A device characterized in that it generates and outputs these stimulus signals and stimuli to the electrode (2).   2. The control system according to claim 1, wherein the control system measures the time course of the activity of the neurons to be decoupled and / or asynchronously directly and / or indirectly through a sensor. Equipment.   The control system (4) measures the time course of the activity of the muscle groups affected by the region to be decoupled and / or desynchronized through at least one sensor (3) of the sensors (3) and / or 3. A device according to claim 2, characterized in that it measures the time course of neuronal activity of a group of neurons associated with a region to be coupled and / or to be asynchronous.   Device according to claim 2 or 3, characterized in that the control system (4) continuously measures the change in activity over time.   Device according to claim 2 or 4, characterized in that the control system (4) measures changes in activity over time at measurement intervals with a limited time.   The control system (4) is a deterministic algorithm and / or a stochastic algorithm and / or an algorithm that combines a deterministic algorithm and a stochastic algorithm for a limited measurement interval and / or interval. The apparatus according to claim 5, wherein the apparatus is controlled by:   7. The device according to claim 2, wherein the control system (4) stores measurement signals.   8. The device according to claim 1, wherein the control system (4) processes the measurement signal.   9. The device according to claim 8, wherein the measurement signal (4) generates a stimulation signal from the processed measurement signal.   10. Device according to claim 8 or 9, characterized in that the control system (4) processes these measurement signals by generating stimulus signals which are time-delayed with respect to the measurement signals.   11. The device according to claim 10, characterized in that the control system (4) generates a stimulation signal whose time delay corresponds to a fraction or a multiple of a fraction of the period of the measurement signal.   12. Device according to claim 10 or 11, characterized in that the control system (4) generates stimulation signals having at least some different time delays.   Device according to any one of claims 8 to 12, characterized in that the control system (4) processes these measurement signals by filtering the measurement signals.   The control system (4) is characterized in that the measurement signal is processed by performing frequency analysis and / or band-pass filtering and / or wavelet analysis and / or Hilbert transform and / or filtering on the measurement signal on a time scale. The apparatus according to any one of claims 8 to 13.   15. The device according to claim 8, wherein the control system (4) processes the measurement signal by coupling and / or transforming the measurement signal linearly and / or non-linearly.   The control system (4) processes the measurement signals by combining and / or transforming the measurement signals linearly and / or non-linearly, in which case the control system (4) is able to combine the measurement signals with each other and / or by itself. 16. The device according to claim 15, characterized in that in particular multiply, divide, add and / or subtract and / or transform the measured signal by other non-linear functions and / or produce absolute values.   17. The device according to any one of claims 8 to 16, characterized in that the control system (4) processes these measurement signals by amplifying the measurement signals.   Device according to any one of claims 8 to 17, characterized in that the control system (4) processes these measurement signals by changing the polarity of the measurement signals.   Device according to any one of claims 8 to 18, characterized in that the control system (4) processes these signals by time-coding the measurement signals.   Device according to claim 19, characterized in that the control system (4) encodes the measurement signal as a pulse train.   21. The apparatus according to claim 20, wherein the control system (4) encodes the measurement signal as a low or high frequency pulse train.   Device according to any one of claims 8 to 21, characterized in that the control system (4) processes these measurement signals by generating stimulation signals generated in the same processing step.   Device according to any one of claims 8 to 21, characterized in that the control system (4) generates at least two stimulation signals in different processing steps.   The control system (4) is a deterministic algorithm and / or a stochastic algorithm and / or an algorithm that combines a deterministic algorithm and a stochastic algorithm, and / or parameters of these processing steps. The device according to claim 8, wherein the device is changed.   25. Device according to any one of the preceding claims, characterized in that the control system (4) limits the maximum amplitude of the stimulation signal.   26. Device according to any one of the preceding claims, characterized in that the control system (4) activates the electrode (2) by stimulation.   27. Device according to claim 26, characterized in that the control system (4) generates a stimulus from a stimulus signal.   The control system (4) multiplies, divides, adds and / or subtracts the measurement signals with each other and / or itself and / or transforms the measurement signals by other non-linear functions and / or produces absolute values. 28. The device according to claim 26 or 27, wherein the device generates a stimulus.   29. Apparatus according to any one of claims 26 to 28, wherein the control system (4) generates a stimulus whose total charge input is approximately zero.   30. Device according to any one of claims 26 to 29, characterized in that the control system (4) controls the application of stimuli.   Device according to claim 30, characterized in that the control system (4) applies the stimulus continuously.   Device according to claim 30, characterized in that the control system (4) applies the stimulus repeatedly.   33. The device according to claim 32, wherein the control system (4) applies stimuli at time-limited stimulation intervals.   The control system (4) controls the period and / or period of the stimulation interval by a deterministic algorithm and / or a stochastic algorithm and / or an algorithm that combines a deterministic algorithm and a stochastic algorithm. 34. The apparatus of claim 33.   35. The device according to any one of claims 1 to 34, characterized in that the control system (4) has additional demand control.   36. Device according to claim 35, characterized in that the control system (4) uses measurement signals and / or stimulation signals for demand control.   37. Device according to claim 35 or 36, characterized in that the control system (4) detects abnormal features in the measurement signal and / or the stimulation signal.   38. Apparatus according to any one of claims 35 to 37, wherein the control system (4) uses the amplitude of the measurement signal and / or the stimulation signal for the required control.   The control system (4) may use the signal itself and / or by using the absolute value of the signal and / or by using a band-pass filtered signal in the frequency domain specific to the disease and / or Or the measured signal and / or by using the absolute value of the bandpass filtered signal in the frequency domain inherent in the disease and / or by using the instantaneous amplitude calculated by the Hilbert transform and / or wavelet analysis 39. Apparatus according to any one of claims 35 to 38, characterized in that the amplitude of the stimulation signal is evaluated.   40. Apparatus according to any one of claims 35 to 39, wherein the control system (4) applies a stimulus when an abnormal feature is detected during measurement and / or stimulation.   41. The control system according to claim 35, characterized in that the control system (4) detects an abnormal feature by detecting that the amplitude threshold of the measurement signal and / or the stimulation signal has been exceeded. Equipment.   The control system (4) is characterized by detecting anomalous features by detecting that the amplitude threshold of the measurement signal and / or the stimulation signal that has been bandpass filtered in the frequency domain inherent in the disease is exceeded. 42. The apparatus according to any one of claims 35 to 41.   43. The control system according to claim 35, characterized in that the control system (4) compares the amplitude of the measurement signal and / or the stimulation signal with a threshold in a moving time window in order to detect abnormal features. The device described in 1.   44. Device according to any one of claims 26 to 43, characterized in that the control system (4) actuates the electrodes (2) with the same stimulus.   44. Device according to any one of claims 26 to 43, characterized in that the control system (4) actuates the electrodes (2) with different stimuli.   46. The control system (4) generates different stimuli, wherein these different stimuli are generated from different stimulus signals and / or by different transformations and / or by combination of stimulus signals. Equipment.   The control system (4) is a deterministic algorithm and / or a stochastic algorithm and / or an algorithm that combines a deterministic algorithm and a stochastic algorithm. 47. Apparatus according to any one of claims 45 to 46, characterized in that the energy input and / or parameters are specifically calculated and changed.   48. Apparatus according to any one of claims 1 to 47, characterized in that the control system (4) changes the parameters of the stimulation signal.   49. The control system according to claim 48, characterized in that the control system (4) changes the parameters of the stimulation signal by adapting the stimulation period T to the instantaneous period of the group of neurons to be decoupled and / or made asynchronous. apparatus.   50. Device according to claim 49, characterized in that the control system (4) calculates the instantaneous period by evaluating the time difference of the trigger points or by a frequency evaluation device.   51. The control system of claim 48, further comprising changing the parameters of the stimulation signal by adapting the stimulation period T to the average period of the group of neurons to be decoupled and / or made asynchronous. The device according to item.   52. Apparatus according to any one of claims 48 to 51, characterized in that the control system (4) changes the parameters of the stimulation signal by adapting the time delay of the stimulation signal to the stimulation period T.   53. Apparatus according to any one of claims 48 to 52, characterized in that the control system (4) changes the parameters of the stimulation signal by adapting the stimulation intensity.   54. Device according to claim 53, characterized in that the control system (4) controls the stimulation intensity with a stimulation intensity between 10 and 1000 of neuronal activity so that proper decoupling and / or asynchrony occurs. .   55. Device according to claim 53 or 54, characterized in that the control system (4) changes the amplitude of the measurement signal in order to control the stimulation intensity.   The control system (4) is programmed so that the relationship between the stimulus intensity and the appearance of abnormal features can be adjusted manually and / or automatically depending on the stimulus result 56. Apparatus according to any one of claims 48 to 55.   57. Apparatus according to any one of claims 1 to 56, characterized in that the control system (4) has an additional manual demand control.   58. Device according to any one of the preceding claims, characterized in that the control system (4) organizes the measurement intervals and the stimulation intervals either overlapping or simultaneously or separately in time.   59. Control system (4) according to any one of claims 1 to 58, characterized in that the group of neurons to be decoupled and / or asynchronous is stimulated directly or indirectly through electrodes (2). Equipment.   The control system stimulates and / or decouples and / or desynchronizes the neurons connected to the neurons to be decoupled and / or desynchronized via the nerve fiber bundle through the electrode (2) 60. The apparatus of claim 59, wherein the apparatus stimulates nerve fiber bundles connected to a group of power neurons.   Control system (4) detects the difference in transmission time between the stimulation position of an electrode (2) and the position of a group of neurons stimulated by this electrode (2) The apparatus of any one of Claims.   62. Control system (4) according to any one of claims 1 to 61, characterized in that it also calculates the associated transmission time when calculating the time delay of the stimulation signal and / or when processing the measurement signal. apparatus.   63. Device according to any one of the preceding claims, characterized in that the electrode (2) is structurally coupled to at least one sensor (3).   64. Device according to any one of claims 1 to 63, characterized in that electrical insulation exists between the control system (4) and the electrode (2).   The device is connected to means for displaying and processing measurement signals and / or stimulation signals and storing data through a telemetry transmitter (11) and a telemetry receiver (12). The apparatus of any one of these.   66. Device according to any one of claims 1 to 65, characterized in that the device is connected to an additional reference database through a telemetry transmitter (11) and a telemetry receiver (12).   67. A control system, wherein the control system is programmed such that the control system controls the steps of performing the operation of the apparatus according to any one of claims 1-66.   67. Use of a device according to any one of claims 1 to 66 for treating diseases caused by and / or associated with firing correlated with abnormalities in a group of neurons.   69. Use of the device of claim 68 for treating Parkinson's disease, essential tremor, ataxia, obsessive compulsive disorder, depression and epilepsy.   14. Use of the control system according to claim 13 for treating diseases caused by and / or associated with firing correlated to abnormalities in a group of neurons.   71. Use of the control system of claim 70 for treating Parkinson's disease, essential tremor, ataxia, obsessive compulsive disorder, depression and epilepsy.   In a method of treating a disease resulting from and / or associated with firing correlated with an abnormality of a neuron population, signals of neuronal activity or physiological characteristics associated with the appearance of a disease pattern are measured, in which case these signals Are applied as electrical stimuli, particularly to brain regions that activate a disease pattern and / or brain regions connected in the vicinity of these brain regions through one electrode after a processing step.   17. The method of claim 16 for treating the diseases Parkinson's disease, essential tremor, ataxia, obsessive compulsive disorder, depression and epilepsy, wherein the neuronal activity or physiological characteristic signal associated with the appearance of the disease pattern is Measured and electrical stimulation signals are generated from these signals, and these electrical stimulation signals are directed to brain regions that trigger disease patterns through electrodes and / or brain regions that are close to these brain regions. A method characterized by being applied.   74. A method according to claim 72 or 73, wherein the stimulation signal is applied with a time delay.   75. Apparatus according to any one of claims 72 to 74, wherein the stimulation signal is applied with a time delay that is a fraction or a multiple of a fraction of the stimulation period T of the measurement signal.   76. Device according to any one of claims 72 to 75, characterized in that the change in activity of the group of neurons to be decoupled and / or made asynchronous is measured directly.   77. Apparatus according to any one of claims 72 to 76, wherein the time course of neuronal activity is measured indirectly. 78. Apparatus according to any one of claims 72 to 77, wherein the stimulation signal is applied continuously, periodically or under required control.
The method according to 6 or 17.   79. Apparatus according to any one of claims 72 to 78, characterized in that the stimulation signal is adapted as a feature according to claims 51-58.   68. A control system according to claim 67 for finding a target point for use or stimulation of the device of any one of claims 1-66.   A method for decoupling a group of neurons to be decoupled from another group of neurons, wherein the group of neurons to be decoupled is stimulated.   82. The method of claim 81, wherein the stimulus is applied electrically.

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